Because major causes of cardiovascular disease have their primary focus in the heart and the arterial circulation the dynamic role of the systemic capacitance system in the regulation of the circulation has received relatively little attention. The venous circulation contains 70-80 percent of the blood volume and through its ability to make rapid adjustments in its dimensions it ensures adequate filling of the heart which in turn is the prime determinant of cardiac output. Our studies, preliminary to this proposal, have helped to define basic aspects of the efferent regulation of systemic capacity. For example, cholinergic stimulation, which had previously been thought to have little effect on the venous circulation, decreases venous return through increasing transhepatic resistance to blood flow which in turn results in splanchnic sequestration of blood. Beta adrenergic receptor stimulation, which relaxes smooth muscle, increases venous return through diminishing resistance in the post sinusoidal region of the liver to splanchnic blood flow. Ouabain, a cardiac glycoside, in contrast to previous findings in studies employing the aglycone acetylstrophanthidin, enhances venous return despite an increase in transhepatic resistance which is mediated by alpha adrenergic receptor stimulation. It is proposed, using a cardiopulmonary bypass preparation with controlled hemodynamics, first, to define carefully the effect of alpha adrenergic receptor stimulation on venous return. It is then planned to examine mechanisms involved in the efferent limb of the stimulation of baroreceptors on the reflex control of venous return. The relative roles of the newly discovered effect of cholinergic influences on venous return and the relative roles of the influences of alpha and beta adrenergic receptor stimulation or withdrawal will be assessed. Similarly, the effect of chemoreceptor stimulation will be defined. Using the above information it is then planned to assess the relative effects on arterial resistance and on systemic venous capacity of vasodilating agents which are commonly used clinically for afterload and preload reduction. It is also planned to extend preliminary observations on the effect of ouabain on venous return to define the effect of digoxin, which is more commonly used clinically, on overall systemic capacity. It is hoped through the proposed studies to gain new insights into this important area of cardiovascular control which will be directly applicable to clinical hemodynamic management.